The present invention relates to benzimidazole compounds having dual nitric oxide synthase (NOS) inhibitory activity and mu opioid receptor agonist activity, and their therapeutic and diagnostic use.
In clinical practice, pain remains fundamentally undertreated (Dray et al., Annu. Rev. Pharmacol. Toxicol. 36:253-280, 1996). In the management of cancer pain, 42% of survey respondents experienced inadequate analgesia (Cleeland et al., N. Engl. J. Med. 330:592-596, 1994). As many as 10-20% of adults suffer from debilitating chronic pain where there may be no discernible pathologic basis for the pain, making conditions such as lower back pain and fibromyalgia difficult to treat. Studies of acute pain management revealed that in the postoperative setting, 77% of adults experienced inadequate pain treatment, with most patients describing the pain as moderate to severe (Warfield and Kahn, Anesthesiology 83:1090-1094, 1995).
While acute pain associated with nociceptive activation by noxious physical, chemical, and thermal stimuli is protective and subsides after the removal of the stimulus, prolonged activation can lead to sensitization of peripheral nociceptors and hyperalgesia. Eventually, prolonged acute pain and hyperalgesia can evolve into chronic pain (Carr and Goudas, Lancet 353:2051-2058, 1999). For example, pain intensity during acute herpes zoster predicts the likelihood of developing postherpetic neuralgia, while rigorous perioperative analgesia for prostatectomy lowers analgesic requirement and improves functional outcome for months afterwards (Carr, JAMA 279:1114-1115, 1998). Thus, acute pain can be the initiation phase of an extensive persistent nociceptive and behavorial cascade triggered by tissue injury which, if not suppressed, leads to progressive central sensitization. Even minor injury can therefore lead to chronic pain.
Opioid analgesics have a long history in the management of pain. Opioids such as morphine and codeine, semi-synthetics such as buprenorphine and oxycodone, or synthetic opioids such as fentanyl are important in the management of acute and chronic pain. Unfortunately opioids are limited in their use for acute and chronic pain treatment due to their known side effects, such as respiratory depression, vomiting, sedation, constipation, addiction, dependency, and the development of tolerance. In addition, neuropathic pain can be particularly insensitive to opioid treatment (Benedetti et al., Pain 74:205-211, 1998) and is still considered to be relatively refractory to opioid analgesics (MacFarlane et al., Pharmacol. Ther. 75:1-19, 1997 and Watson, Clin. J. Pain 16:S49-S55, 2000). While dose escalation can overcome reduced opioid effectiveness, it is limited by increased side effects and tolerance.
Nitric oxide (NO) has diverse roles both in normal and pathological processes, including the regulation of blood pressure, in neurotransmission, and in the macrophage defense systems (Snyder et al., Scientific American, May 1992:68). NO is synthesized by three isoforms of nitric oxide synthase; a constitutive form in endothelial cells (eNOS), a constitutive form in neuronal cells (nNOS), and an inducible form found in macrophage cells (iNOS). These enzymes are homodimeric proteins that catalyze a five-electron oxidation of L-arginine, yielding NO and citrulline. The role of NO produced by each of the NOS isoforms is quite unique. Overstimulation or overproduction of individual NOS isoforms plays a role in several disorders, including septic shock, arthritis, diabetes, ischemia-reperfusion injury, pain, and various neurodegenerative diseases (Kerwin, et al., J. Med. Chem. 38:4343, 1995).
Evidence suggests that the combination of an opioid analgesic with an inhibitor of neuronal nitric oxide synthase (nNOS) would be beneficial. Morphine administration is known to activate the NOS system and limits the analgesic action of this drug (Li and Clark, Mol. Brain. Res. 95(1-2):96-102, 2001; Machelska et al., NeuroReport 8:2743-2747, 1997; Wong et al., Br. J. Anaesth. 85:587, 2000; and Xiangqi and Clark, Mol. Brain. Res. 95:96-102, 2001). However, it has been shown that the combined systemic administration of morphine and L-NAME can attenuate mechanical and cold allodynia at subthreshold doses where neither drug administered alone was effective (Ulugol et al., Neurosci. Res. Com. 30(3):143-153, 2002). The effect of L-NAME co-administration on morphine analgesia appears to be mediated by nNOS, as L-NAME loses is ability to potentiate morphine analgesia in nNOS null-mutant mice (Clark and Xiangqi vide supra). Enhanced analgesia has been demonstrated in a tail-flick or paw pressure model using coadministration of L-NAME or 7-NI with either mu-, delta-, or kappa-selective opioid agonists (Machelska et al., J. Pharmacol. Exp. Ther. 282:977-984, 1997).
Evidence also suggests that NOS inhibitors would be useful for preventing opioid tolerance and dependence. Tolerance and dependence resulting from chronic exposure to opioid analgesics, such as morphine, is related to adaptive changes, such as opioid receptor downregulation, receptor internalization, and uncoupling from inhibitory G proteins. Tolerance and dependence can also result from receptors involved in cAMP signal transduction being densensitized, up-regulated, or supersensitized. Other side effects of chronic opioid administration include the development of opioid-induced hyperalgesia (OIH). In a murine model of OIH, the NOS inhibitor L-NAME and NMDA antagonist MK-901 dose-dependently reduced OIH (Li et al., Mol. Brain. Res. 86(1,2):56-62, 2001).
Thus, the combination of a selective nNOS inhibitor with an opioid analgesic is expected to enhance opioid analgesia and prevent the development of opioid tolerance, prevent the development of opioid-induced hyperalgesia, and/or minimize side effects. While many drug combinations with opioids have been shown to enhance analgesia or reduce side effects, fewer examples are known for which opioid and non-opioid activity are contained within a single drug and none appear to exist for compounds possessing both NOS inhibitory activity and opioid agonist or antagonist activity.